Alzheimer's disease (AD) is one of the major public health concerns as seemingly healthy populations age. AD may cost American society more than $200 billion dollars per year. Accumulation of amyloid-?A?and phosphorylated tau in the brain is proposed to be key factors in a complex neurodegenerative cascade that eventually leads to widespread brain organ failure resulting in symptomatic AD. Increasing data suggest that accumulation of Aaggregates in the cerebrovasculature and the resulting vessel dysfunction contribute to degenerative cascades by diminishing cerebral blood flow (CBF) and by impairing A?learance. Advanced age is, by far, the greatest risk factor for AD. Rapamycin inhibits a key regulator of cellular metabolism (the target-of-rapamycin, TOR) and is the first drug that has been experimentally proven to slow aging in mice. Consistent with these observations, we have shown that rapamycin halts and even rescues AD- like memory deficits in transgenic hAPP(J20) mice modeling the disease (Spilman et al 2009, Lin et al 2013), and this was also documented in other AD models (Caccamo et al 2010). Further, we found that rapamycin decreased Alevels in the brain and linked this decrease to the activation of autophagy. More recent studies from our lab (Lin et al 2013) indicate that beneficial effects of rapamycin also involve the restoration vascular density and cerebral blood flow, an effect dependent on the activation of endothelial nitric oxide synthase (eNOS), a major regulator of vascular function, in brain vasculature. Thus rapamycin may enhance memory by breaking a vicious cycle initiated by Aaggregates in brain that is reinforced by A?nduced vascular deterioration. We will test the hypothesis that rapamycin can synergistically have beneficial actions on AD relevant phenotypes in mice by decreasing A?nduced vascular damage and by restoring vascular integrity through eNOS with the following aims: (1) Determine whether pharmacologically lowering of A?ith a ?ecretase inhibitor can reduce vascular damage to the same extent as rapamycin and whether combination therapy with rapamycin and a BSI has a synergistic effect on vascular function; (2) Evaluate mechanisms whereby rapamycin could facilitate the removal of A?y the cerebrovasculature; and (3) Explore whether rapamycin restores vascular integrity and function through the activation of eNOS. The relevance of this project is that it will further establish the therapeutic potential for rapamycin or potentially other TOR inhibitors in the treatment of AD, and will also increase our understanding of mechanisms of rapamycin action in AD brain. Furthermore, our project has extrinsic merit in the insight it will provide on the potential of combination therapies, which may be key to effective treatment of AD. TOR inhibitors are FDA- approved and used in the clinic, and a recent pilot study by our collaborators at the South Texas VA suggets safety of rapamycin as a single treatment in healthy elderly, thus our research has immediate translational potential for Veterans suffering from AD since clinical trials would be feasible in the near future. Because rapamycin prevents brain vascular dysfunction, a universal feature of aging, our findings have the potential to be applicable to othe age-related neuropathologies such as vascular dementia and forms of Parkinson's disease.